Lung cancer is responsible for nearly one-third of all cancer-related death in the U.S., and the cure rates remain low. Thus, there is a need to develop compounds that can prevent the disease in individuals at risk. Cigarette smoking, obstructive pulmonary disease, and age are the overwhelming risk factors. Persons that have quit smoking remain at an increased risk for lung cancer for lifetime that is proportional to the amount of cigarettes smoked. Former smokers are a particularly attractive target population for chemoprevention with pharmacological agents. A number of compounds have been tested but trials to date have not resulted in a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials, which evaluated beta-carotene in current and former smokers, resulted in an increase of incidence and mortality from lung cancer. Subgroup analyses of these studies and other related published reports suggest that the clinical and biologic responses to chemopreventive agents differ between active and former smokers. Nationally, the focus of lung cancer chemoprevention is on inhibitors of inflammatory response pathways and growth factor signaling pathways and the use of intermediate biomarkers as primary trial endpoints. A novel agent with antiproliferative, proapoptotic, and minimal toxic effects is enzastaurin (LY317615). It is an oral protein kinase C (PKC) inhibitor currently undergoing clinical efficacy testing in phase II and III trials in patients with a variety of malignancies. To test the clinical utility of this agent in lung cancer prevention, we will conduct a double-blind, placebo-controlled, randomized phase lib trial in former smokers. A surrogate marker of lung cancer risk, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others, in particular components of the DMA replication origin licensing complex, will also be explored as surrogate trial endpoints. The data generated by these investigations will not only determine the efficacy of enzastaurin as a chemopreventive agent for lung cancer, but also provide important analytical leads for future studies.